Antiepileptic Drug Targets: An Update on Ion Channels

Different mechanisms of action have been proposed to explain the effects of antiepileptic drugs (AEDs) including modulation of voltage‐dependent sodium calcium and potassium channels, enhancement of γ‐aminobutyric acid (GABA)‐mediated neuronal inhibition, and reduction in glutamate‐mediated excitatory transmission. Recent advances in understanding the physiology of ion channels and genetics basis of epilepsies have given insight into various molecular targets for AEDs. Conventional AEDs predominantly target voltage‐ and ligand‐gated ion channels including the α subunits of voltage‐gated Na+ channels, T‐type, and α2‐δ subunits of the voltage‐gated Ca2+ channels, A‐ or M‐type voltage‐gated K+ channels, the γ‐aminobutyric acid (GABA) receptor channel complex, and ionotropic glutamatergic receptors. Molecular cloning of ion channel subunit proteins and studies in epilepsy models suggest additional targets including hyperpolarization‐activated cyclic nucleotide‐gated cation (HCN) channel subunits, responsible for hyperpolarization‐activated current (Ih), voltage‐gated chloride channels, and acid‐sensing ion channels. This chapter gives an update on voltage‐ and ligand‐gated ion channels, discussing their structures, functions, and relevance as potential targets for AEDs

Analgesic and Anti-Inflammatory activities of Rothmannia Longiflora Salisb In Mice And Rats

Abstract: In this study, the analgesic and anti-inflammatory activities of the methanolic leaf extract of Rothmannialongiflora were investigated. The methanolic leaf extract of the plant at the doses of 250, 500, and 1000mg/kg orally was evaluated for analgesic activity using acetic acid-induced writhing test, hot plate test and formalin test. The anti-inflammatory potential of the extract was evaluated using carrageenan-induced paw oedema test in rats. The methanolic leaf extract exhibited significant dose dependent analgesic and antiinflammatory effects comparable to piroxicam (20mg/kg body weight orally), which is a standard analgesic and anti-inflammatory drug. The preliminary phytochemical screening of the methanolic leaf extract of Rothmannialongiflora revealed the presence of flavonoids, tannins, saponins, glycosides, steroids/terpanoids, and carbohydrates. The oral median lethal dose (LD 50 ) of the extract in mice and rats were found to be greater than 5000mg/kg, suggesting that the methanolic leaf extract of Rothmannialongiflora is non-toxic. The present findings suggest that the methanolic leaf extract of the plant possesses analgesic and anti-inflammatory activities, and supports the ethno medical claims of the use of the plant in the management of pain and inflammatory conditions

New Insights Into the Anticonvulsant Effects of Essential Oil From Melissa officinalis L. (Lemon Balm)

Melissa officinalis L. is used in traditional European and Iranian folk medicines to treat a plethora of neurological diseases including epilepsy. We utilized the in vitro and in vivo models of epilepsy to probe the anticonvulsant potentials of essential oil from M. officinalis (MO) to gain insight into the scientific basis for its applications in traditional medicine for the management of convulsive disorders. MO was evaluated for effects on maximal electroshock (MES) and pentylenetetrazole (PTZ) -induced seizures in mice, on 4–aminopyridine (4-AP)-brain slice model of epilepsy and sustained repetitive firing of current clamped neurons; and its ameliorative effects were examined on seizure severity, anxiety, depression, cognitive dysfunction, oxidative stress and neuronal cell loss in PTZ-kindled rats. MO reversibly blocked spontaneous ictal-like discharges in the 4-AP-brain slice model of epilepsy and secondary spikes from sustained repetitive firing, suggesting anticonvulsant effects and voltage-gated sodium channel blockade. MO protected mice from PTZ– and MES–induced seizures and mortality, and ameliorated seizure severity, fear-avoidance, depressive-like behavior, cognitive deficits, oxidative stress and neuronal cell loss in PTZ–kindled rats. The findings warrant further study for the potential use of MO and/or its constituent(s) as adjunctive therapy for epileptic patients

Anti-hyperglycaemic activity of tuber extract of Chlorophytum alismifolium Baker in streptozotocin-induced hyperglycaemic rats

The tubers of Chlorophytum alismifolium (Liliaceae) are widely used in Nigerian Herbal Medicine to treat diabetes mellitus and their efficacy is widely acclaimed among the rural communities of Northern Nigeria. This study was aimed at investigating the antihyperglycaemic potential of the tuber extract of Chlorophytum alismifolium (CAE) in streptozotocin-induced hyperglycaemic rats. Phytochemical screening and oral median lethal dose (LD50) estimation of CAE in rats were carried out. Antihyperglycaemic screening of the extract (at oral doses of 150, 300 and 600 mg/kg) was performed using normal and streptozotocin-induced hyperglycaemic rats for 28 days. Fasting blood glucose levels were measured and serum lipids were analyzed. Liver, kidney, heart and pancreatic tissues were examined for histopathological damages using standard histological processing. Phytochemical screening revealed the presence alkaloids, saponins, flavonoids, triterpenes and glycosides. Oral LD50 was estimated to be >5000 mg/kg body weight in rats. C. alismifolium extract at all the doses tested showed blood glucose lowering effect. Statistical significant (p < .01) blood glucose lowering effect at 150 mg/kg on day 21, at 300 mg/kg on days 21 and 28 (p < .001 and p < .01 respectively) and 600 mg/kg on days 7, 14, 21 and 28 (p < .05, p < .01, p < .001 and p < .01 respectively) was produced by the extract. The extract also reduced the levels of total cholesterol, triglycerides and low density lipoprotein. Histopathological examination of the pancreas showed restoration of pancreatic islet cells at the doses of 300 and 600 mg/kg of the extract. In conclusion, the results obtained suggest the tuber extract of Chlorophytum alismifolium possesses antihyperglycaemic activity

Postsynaptic Dopamine (D2)-Receptor May be Involved in the Behavioral Activities of Artemisinin in Rodents

Behavioural effects of Artemisinin (AR) were studied on spontaneous motor activity (SMA), exploratory behaviour (EB), apomorphine induced stereo- typed behaviour (ASB) in mice and bromocriptine induced hyperactivity (BIH) in short-term reserpinized(STR) mice. AR (50 and 100 mg/kg, i.p.) significantly (p \u3c 0.05) reduced the SMA, EB and attenuated ASB mice. The STR Mice showed a decreased in locomotor activity (LA), which was activated by bromocriptine (5 mg/kg, i.p.). AR attenuated BIH in the STR mice. The results suggest that artemisinin possesses central inhibitory property, which may be mediated via postsynaptic dopamin E (D2)-receptor antagonism in the brain stem area

Behavioural Effect of \u3cem\u3ePavetta crassipes\u3c/em\u3e Extract on Rodents

The effects of the ethanol extract of Pavetta crassipes on the central nervous system (CNS) and on actions of some selected centrally acting drugs were studied in mice and rats. These studies were carried out using the spontaneous motor activity (SMA), amphetamine-induced hyperactivity and stereotyped behaviour,pentobarbital-induced hypnosis and exploratory activity, apomorphine-induced climbing and haloperidol-induced catalepsy in rats. The results demonstrated that the extract of P. crassipes dose-dependently decreased SMA in mice and attenuated amphetamine-induced hyperactivity and the different episodes of stereotypic behavioural patterns induced by amphetamine. In addition, the extract decreased the number of head dips in the exploratory activity test and potentiated pentobarbital-induced sleeping time in rats. Furthermore, the extract inhibited apomorphine-induced climbing in mice and potentiated haloperidol-induced catalepsy in rats. Our results suggest that the extract of P. crassipes contains biologically active substance(s) that might be acting centrally through the inhibition of dopaminergic pathway or a system linked to this pathway to mediate the observed pharmacological effects

Evaluation of the anti-nociceptive profile of essential oil from Melissa officinalis L. (lemon balm) in acute and chronic pain models

Ethnopharmacological relevanceMelissa officinalis L. (Lamiaceae) is a medicinal plant native to Mediterranean regions and found in other parts of the world. Extracts and essential oil from this widely cultivated culinary medicinal herb are used in traditional medicine to manage a variety of disorders that include epilepsy and pain.Aim of the studyTo assess the anti-nociceptive potentials of Melissa officinalis essential oil (MO) and probe the involvement of adrenergic, opioidergic, serotonergic and potassium adenosine triphosphate (KATP) mechanisms in its anti-nociceptive effects.Material and methodsWe employed formalin-, acetic acid and hot plate-induced nociception to study the acute anti-nociceptive effects of MO. The sciatic nerve injury (CCI) model of neuropathic pain was utilized to study the anti-nociceptive effects of MO on chronic pain. Effects of MO on anxiety, cognitive deficits, oxidative stress and inflammation in the CCI rats were evaluated on elevated plus maze, open field test, novel object recognition, oxidative stress parameters and pro-inflammatory cytokines, respectively. The possible mechanism(s) of MO's anti-nociceptive effects were elucidated using prazosin, yohimbine, propranolol, glibenclimide, naloxone and metergoline, which are acknowledged antagonists for α1–, α2– and β–adrenergic, potassium adenosine triphosphate (KATP), opioidergic and serotonergic systems, respectively.ResultsMO significantly attenuated acetic acid- and formalin-induced nociception; prolonged the mean reaction time of rats on hot plate before and following sciatic nerve chronic injury (CCI). MO ameliorated anxiety, cognitive deficits and oxidative stress, reduced pro-inflammatory cytokine levels and produced a near total restoration of injured sciatic nerves in CCI rats. Naloxone, metergoline and glibenclimide significantly blocked, while prazosin, yohimbine and popranolol failed to block the anti-nociceptive effects of MO in formalin-induced nociception.ConclusionsMO contains biologically active compounds with potential anti-nociceptive properties that modulate KATP, opioidergic and serotonergic pathways. These support the development of bioactive compounds from MO as anti-nociceptive agents

Anticonvulsant Properties of Saponins from Ficus platyphylla Stem Bark

Preparations of Ficus platyphylla have been used in Nigerian traditional medicine for the management ofepilepsy for many years and their efficacy is widely acclaimed among the Hausa communities of northern Nigeria. The anticonvulsant properties of the saponin rich fraction (SFG) obtained from the methanol extract of F. platyphylla stem bark were studied on pentylenetetrazole-, strychnine- and maximal electroshockseizures in mice. Effects of SFG were also examined in murine models for neurological disease and on relevant in vitro targets for anticonvulsant drugs. SFG protected mice against pentylenetetrazole- and strychnine-induced seizures; and significantly delayed the onset of myoclonic jerks and tonic seizures. SFG failed to protect mice against maximal electroshock seizures at doses tested. SFG neither abolished the spontaneous discharges induced by 4-aminopyridine in a neonatal rat brain slice model of tonic–clonic epilepsy nor could it modulate chloride currents through GABAA receptor channel complex in cultured cortical cells. However, it was able to non-selectively suppress excitatory and inhibitory synaptic traffic, blocked sustained repetitive firing (SRF) and spontaneous action potential firing in these cultured cells. Our results provide scientific evidence that F. platyphylla stem bark may contain psychoactive principles with potential anticonvulsant properties. SFG impaired membrane excitability; a property shared by most anticonvulsants particularly the voltage-gated sodium channel (VGSC) blocking drugs, thus supporting the isolation and development of the saponin components of this plant as anticonvulsant agents